Transporter enhanced corticosteroid activity

Abstract

Methods and compositions for enhancing the activity and/or duration of action of loteprednol etabonate and other soft anti-inflammatory steroids of the haloalkyl 17α-alkoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate type and the corresponding Δ 1,4 -compounds are described. The enhancing agents have the formula: wherein Z 1 is carbonyl, β-hydroxymethylene or methylene; R 2 is H, —OH or —OCOR 3 wherein R 3 is C 1 -C 5 alkyl; Y is —OH, —SH or —OCOR 4 wherein R 4 is C 1 -C 5 alkyl, cyclopentylethyl or diethylaminoethyl; and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated.

1. A composition comprising:
 (a) loteprednol etabonate; and 
 (b) a compound having the formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 Z 1  is β-hydroxymethylene or methylene; 
 R 2  is H or —OH; 
 Y is —OH or —OCOR 4 , wherein R 4  is C 1  alkyl; 
 and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated; 
 the compound of formula (II) being selected from the group consisting of hydrocortisone, hydrocortisone acetate, prednisolone, prednisolone acetate, corticosterone, corticosterone 21-acetate, 11-deoxycorticosterone and 11-deoxyhydrocortisone; 
 in a combined synergistic anti-inflammatory effective amount; 
 the amount of compound of formula (II) being sufficient to enhance the anti-inflammatory activity or duration of action, or both, of loteprednol etabonate, said amount of said compound of formula (II) being insufficient alone to have anti-inflammatory activity; 
 wherein the molar ratio of the compound of formula (II) to loteprednol etabonate is from about 2:1 to about 0.05:1; 
 
       with the proviso that the composition excludes any compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R is H or C 1 -C 4  alkyl; 
 Z 2  is carbonyl or β-hydroxymethylene; 
 X 1  is —O— or —S—; 
 R 5  is —OH, —OR 6 , —OCOOR 6  or —OCOR 7  wherein R 6  is C 1 -C 4  alkyl and R 7  is C 1 -C 4  alkyl, fluoromethyl or chloromethyl; 
 and the dotted line is defined as above; 
 with the proviso that when R is C 1 -C 4  alkyl, then R 5  is —OH. 
 
     
     
       2. The composition according to  claim 1 , wherein the compound of formula (II) is hydrocortisone. 
     
     
       3. A composition according to  claim 1 , wherein the molar ratio of compound of formula (II) to loteprednol etabonate is from about 1:1 to about 0.2:1. 
     
     
       4. A composition according to  claim 1 , wherein the molar ratio of compound of formula (II) to loteprednol etabonate is from about 1:1 to about 0.5:1. 
     
     
       5. A pharmaceutical composition comprising:
 (1) a combined synergistic anti-inflammatory effective amount of:
 (a) loteprednol etabonate; and 
 (b) a compound having the formula: 
 
 
       
         
           
           
               
               
           
         
       
       wherein Z 1  is β-hydroxymethylene or methylene; R 2  is H or —OH Y is —OH or —OCOR 4  wherein R 4  is C 1  alkyl; and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated, the compound of formula (II) being selected from the group consisting of hydrocortisone, hydrocortisone acetate, prednisolone, prednisolone acetate, corticosterone, corticosterone 21-acetate, 11-deoxycorticosterone and 11-deoxyhydrocortisone, the amount of compound of formula (II) being sufficient to enhance the anti-inflammatory activity or duration of action, or both, of loteprednol etabonate, said amount of said compound of formula (II) being insufficient alone to have anti-inflammatory activity;
 wherein the molar ratio of the compound of formula (II) to loteprednol etabonate is from about 2:1 to about 0.05:1; 
 and 
 (2) a non-toxic, pharmaceutically acceptable carrier therefor suitable for topical or other local application; 
 
       with the proviso that the composition excludes any compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R is H or C 1 -C 4  alkyl; 
 Z 2  is carbonyl or β-hydroxymethylene; 
 X 1  is —O— or —S—; 
 R 5  is —OH, —OR 6 , —OCOOR 6  or —OCOR 7  wherein R 6  is C 1 -C 4  alkyl and R 7  is C 1 -C 4  alkyl, fluoromethyl or chloromethyl; 
 and the dotted line is defined as above; 
 with the proviso that when R is C 1 -C 4  alkyl, then R 5  is —OH. 
 
     
     
       6. A composition according to  claim 5 , formulated as: an ointment, gel, lotion or cream; a powder; drops or a spray; a suppository, retention enema or foam; a chewable or suckable tablet or pellet; an aerosol; a nebulized or powdered formulation for oral inhalation; a parenteral or other injectable dosage form; or an oral dosage form which releases the active ingredients in the upper or lower intestines. 
     
     
       7. A composition according to  claim 5 , formulated in a dermal or transdermal patch. 
     
     
       8. The composition according to  claim 5 , wherein the compound of formula (II) is hydrocortisone. 
     
     
       9. A composition according to  claim 5 , wherein the molar ratio of compound of formula (II) to loteprednol etabonate is from about 1:1 to about 0.2:1. 
     
     
       10. A composition according to  claim 5 , wherein the molar ratio of compound of formula (II) to loteprednol etabonate is from about 1:1 to 0.5:1. 
     
     
       11. A method for enhancing the anti-inflammatory activity or duration of action, or both, of loteprednol etabonate 
       following topical or other local administration of said compound to a warm-blooded animal in need of treatment to alleviate a topical or other localized inflammatory response, said method comprising topically or otherwise locally administering to said animal an anti-inflammatory effective amount of a composition according to  claim 1 . 
     
     
       12. A method for enhancing the anti-inflammatory activity or duration of action, or both, of loteprednol etabonate following topical or other local administration thereof to a warm blooded animal in need of treatment to alleviate a topical or other localized inflammatory response, said method comprising topically or otherwise locally administering to said animal an anti-inflammatory effective amount of a composition according to  claim 5 . 
     
     
       13. A method for alleviating inflammation in or on a warm-blooded animal exhibiting a topical or other localized inflammatory response, which comprises topically or otherwise locally administering to said animal an anti-inflammatory effective amount of a composition as claimed in  claim 1 . 
     
     
       14. A method according to  claim 13 , comprising administering said anti-inflammatory effective amount to the eye or eyes of a warm-blooded animal exhibiting an ophthalmic inflammatory response; to the nasal mucosa of a warm-blooded animal exhibiting a nasal inflammatory response; by oral inhalation to a warm-blooded animal exhibiting an asthmatic inflammatory response; to the rectal mucosa of a warm-blooded animal exhibiting inflammation of the upper or lower intestine or rectum; orally to a warm-blooded animal exhibiting an inflammatory response of the upper or lower intestines; to the ear or ears of a warm-blooded animal exhibiting an otic inflammatory response; by injection into the joint or joints of a warm-blooded animal exhibiting an arthritic response; to the skin of a warm-blooded animal exhibiting a dermal inflammatory response; or orally to a warm-blooded animal exhibiting an oral, gingival or throat inflammatory response. 
     
     
       15. A method for alleviating inflammation in or on a warm-blooded animal exhibiting a topical or other localized inflammatory response, which comprises topically or otherwise locally administering to said animal an anti-inflammatory effective amount of a composition as claimed in  claim 5 . 
     
     
       16. A method according to  claim 15 , comprising administering said anti-inflammatory effective amount to the eye or eyes of a warm-blooded animal exhibiting an ophthalmic inflammatory response; to the nasal mucosa of a warm-blooded animal exhibiting a nasal inflammatory response; by oral inhalation to a warm-blooded animal exhibiting an asthmatic inflammatory response; to the rectal mucosa of a warm-blooded animal exhibiting inflammation of the upper or lower intestine or rectum; orally to a warm-blooded animal exhibiting an inflammatory response of the upper or lower intestines; to the ear or ears of a warm-blooded animal exhibiting an otic inflammatory response; by injection into the joint or joints of a warm-blooded animal exhibiting an arthritic response; to the skin of a warm-blooded animal exhibiting a dermal inflammatory response; or orally to a warm-blooded animal exhibiting an oral, gingival or throat inflammatory response. 
     
     
       17. A method according to  claim 13 , wherein the molar ratio of compound of formula (II) to loteprednol etabonate is from about 1:1 to about 0.2:1. 
     
     
       18. A method according to  claim 13 , wherein the molar ratio of compound of formula (II) to loteprednol etabonate is from about 1:1 to about 0.5:1. 
     
     
       19. A method according to  claim 15 , wherein the molar ratio of compound of formula (II) to loteprednol etabonate is from about 1:1 to about 0.2:1. 
     
     
       20. A method according to  claim 15 , wherein the molar ratio of compound of formula (II) to loteprednol etabonate is from about 1:1 to about 0.5:1.